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A Multicenter, open-labelled, randomized controlled trial to evaluate the efficacy and safety of therapeutic plasma exchange in subjects with snakebite associated thrombotic microangiopathy compared to those receiving standard of care alone

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SLCTR Registration Number

SLCTR/2024/008


Date of Registration

15 Mar 2024

The date of last modification

Mar 15, 2024



Application Summary


Scientific Title of Trial

A Multicenter, open-labelled, randomized controlled trial to evaluate the efficacy and safety of therapeutic plasma exchange in subjects with snakebite associated thrombotic microangiopathy compared to those receiving standard of care alone


Public Title of Trial

A Multicenter, open-labelled, randomized controlled trial to evaluate the efficacy and safety of therapeutic plasma exchange in subjects with snakebite associated thrombotic microangiopathy compared to those receiving standard of care alone


Disease or Health Condition(s) Studied

Snakebite associated thrombotic microangiopathy


Scientific Acronym

None


Public Acronym

None


Brief title

A randomized clinical trial to evaluate efficacy and safety of therapeutic plasma exchange in snakebite associated thrombotic microangiopathy


Universal Trial Number

U1111-1297-0734


Any other number(s) assigned to the trial and issuing authority

EC-23-089:Faculty of Medicine, UoC


Trial Details


What is the research question being addressed?

Is Therapeutic Plasma Exchange (TPE) effective and safe in treating snakebite associated thrombotic microangiopathy compared to standard therapy alone?’


Type of study

Interventional


Study design

Allocation

Randomized controlled trial


Masking

Masking not used : Data analysts


Control

Standard therapy/practice


Assignment

Parallel


Purpose

Treatment


Study Phase

Not Applicable


Intervention(s) planned

Study setting: At five hospitals; NHSL -Colombo, TH Peradeniya, NHSL- Kandy, TH Anuradhapura, and TH Kurunegala.

Study population: All patients who have been bitten by a RV (Russell's Viper) or HNV (Humped Nose Viper) and are admitted directly or transferred from other hospitals within 5 days of a RV or HNV bite and showing evidence of Thrombotic Microangiopathy (TMA) with or without AKI will be included.

Consented patients diagnosed with TMA will be randomized into either control arm of treatment arm.

Study groups: Treatment arm: Patients who receive Therapeutic Plasma Exchange (TPE) along with standard care. Control arm: Patients who receive standard care except TPE administration.

Method of randomization: Block randomization (Blocks of four) method. Separate blocks will be allocated for each study site, with equal number of participants in each arm. Computer-based random number generation facilitates simultaneous allocation of treatments for multiple participants, supporting parallel assignment. Allocation concealment will prevent bias. Allocation consignment involves contacting a central investigator after participant consent, indicating parallel allocation to treatment arms.

Person responsible for allocation: An investigator from Faculty of Medicine, University of Colombo) who is not directly involved with the intervention will prepare the computer based random number list and inform the study sites regarding patient allocation

Allocation concealment: Sequence will be concealed from the investigators at the hospitals and study participants to prevent the selection bias.

Treatment Protocol:

1) Control arm Patients will receive only the standard care as described below. Dialysis and Fresh frozen plasma (FFP) administration will be at the discretion of the treating physician.

Standard care Protocol - Patients will go through a clinical assessment along with laboratory values (full blood count, blood picture, coagulation profile, renal and liver function profile and electrolytes) - Monitor vital signs, oxygen saturation, and level of consciousness, blood pressure, pulse rate and body temperature - Polyvalent equine antivenom (Vinus bioproduct, Hyderabad or Serum Institute of India) will be administered to all the patients who had clinical or laboratory evidence of systemic envenoming following RV bites, at the admission to the hospital based on local guidelines. Patients with HNV will be treated with other available active treatments as currently available Indian Polyvalent antivenom is not proved to be effective.

Supportive care provided; - Pain management: pain relief using analgesics - Management of swelling by elevating affected limb - Wound care - Administer supplemental oxygen if there are signs of respiratory distress - Establish intravenous access for fluid resuscitation and medication administration. - Maintain hydration and electrolyte balance - Treat complications such as bleeding disorders, allergic reactions and infections including the use of blood products and antibiotics at the discretion of the treating physician - Tetanus toxoid will be given as a standard treatment on the basis of having puncture wound or tissue damage to preventing any bacterial infection.

In severe cases with systemic envenomation - Management of the patient in an intensive care unit if required - Treat organ dysfunction including dialysis for Acute Kidney Injury (AKI) - Provide appropriate follow-up care to monitor for delayed complications or relapses.

Dialysis: AKI patients needing renal replacement therapy will be hemodialyzed using a low flux hemodialyzer with standard settings every 2 to 3 days until dialysis independence or death occurs.

FFP administration: At the discretion of the treating physician, patients will receive FFP when indicated. FFP is generally indicated in snakebite-associated coagulopathy when (Prothrombin time) PT and/or Activated partial thromboplastin time (APPT) >1·5 times normal and there is associated bleeding.

Volume of FFP administration will be based on the patient's weight, the clinical indication, and the desired correction of coagulation parameters. The generally practiced adult therapeutic dose of FFP is 40 ml/kg to replace clotting factors.

  1. Treatment arm Patients will receive TPE along with the standard care as described below.

Protocol for TPE

  • TPE performed using an automated blood cell separator to ensure fluid balance and maintain a normal plasma volume. This will require the insertion of a femoral or jugular venous line to allow adequate blood flow.
  • Volume of plasma to be removed will be calculated as 1 -1.5 times plasma volume of the patient. FFP will used as the 100% replacement fluid in TPE. If the patient is having AKI, 90% replacement by FFP will be done to maintain a negative fluid balance to prevent fluid overload.
  • Three TPE cycles will be administered within 5 days of diagnosis of TMA. If the patient is on dialysis due to AKI associated with snakebite, TPE will be done on alternative days3.

Therapeutic plasma exchange

Administration: A femoral or jugular venous line will be inserted and therapeutic plasma exchange will be done using an automated blood cell separator.

Volume: Patient’s height, weight and haemotocrit will be entered to machine and the machine automatically calculates the patient’s blood volume and plasma volume. (Volume of plasma to be removed will be calculated as 1 -1.5 times plasma volume of the patient. )

Replacement fluid: FFP will be used as the replacement fluid. If the patient is having AKI, 90% replacement by FFP will be done.

Frequency: Three TPE cycles will be administered within 5 days of diagnosis of TMA. If the patient is on dialysis due to AKI associated with snakebite, TPE will be done on alternative days.


Inclusion criteria

  1. All males and females
  2. All patients with age equal to more than 18 years
  3. Patients diagnosed with TMA with or without AKI following RV or HNV bite
  4. Patients directly admitted or transferred to the hospital within 5 days of the snakebite

Criteria used for diagnosis of TMA: TMA is confirmed by the presence of microangiopathic haemolytic anaemia (MAHA) with > 1.0% schistocytes in peripheral blood film examination with absolute thrombocytopenia < 150 x 109 /L or > 25% reduced platelet count from baseline, with or without AKI. At each study site, the local hematologists will be provided with a protocol to identify TMA by recognizing and calculating schistocytes in the peripheral blood


Exclusion criteria

  1. Patients having known allergy to drug prodcuts
  2. Pregnancy
  3. Patients having allergic reactions to blood products
  4. Patients with pre-existing chronic kidney disease with an eGFR <30 ml/min/1.73m2


Primary outcome(s)

1.

"Survival" defined as whether the patient is alive or deceased at the three-month mark.

Tool used: Medical records or direct follow up

[

At the time of discharge and 3 months after discharge from the hospital

]
2.

"Dialysis dependency" defined as whether the patient requires ongoing dialysis treatments for kidney function

[

At the time of discharge and 3 months after discharge from the hospital

]
3.

Glomerular filtration rate (eGFR) <30 ml/min/1.73m2
[An eGFR <30 ml/min/1.73m2 signifies severe kidney dysfunction]

[

At the time of discharge and 3 months after discharge from the hospital

]

Secondary outcome(s)

1.

Number of blood transfusions

[

At the time of discharge from the hospital

]
2.

Number of dialysis received

[

At the time of discharge from the hospital

]
3.

Duration of the hospital stay

[

At the time of discharge from the hospital

]

Target number/sample size

Total 140 (70 in each arm)


Countries of recruitment

Sri Lanka


Anticipated start date

2024-03-15


Anticipated end date

2025-09-30


Date of first enrollment


Date of study completion


Recruitment status

Pending


Funding source


Regulatory approvals

Not applicable



State of Ethics Review Approval


Status

Approved


Date of Approval

2023-12-21


Approval number

EC-23-089


Details of Ethics Review Committee

Name: Ethics Review Committee, Faculty of Medicine, University of Colombo.
Institutional Address:No 25, Kynsey Rd, Colombo 08
Telephone:+94 112 695 300 ext: 240
Email: erc@med.cmb.ac.lk

Contact & Sponsor Information


Contact person for Scientific Queries/Principal Investigator

Professor Eranga Wijewickrama
Professor
Department of Clinical Medicine, Faculty of Medicine, University of Colombo

0777250214

erangasw@clinmed.cmb.ac.lk

Contact Person for Public Queries

Professor Eranga Wijewickrama
Professor
Department of Clinical Medicine, Faculty of Medicine, University of Colombo

0777250214

erangasw@clinmed.cmb.ac.lk


Primary study sponsor/organization







Secondary study sponsor (If any)







Trial Completion details


Do the investigators plan to share identified individual clinical trial participant-level data (IPD)?

No


IPD sharing plan description


Study protocol available

No


Protocol version and date

Not Available


Protocol URL

Not Available


Results summary available

No


Date of posting results


Date of study completion


Final sample size


Date of first publication


Link to results


Brief summary of results